Elevated intraocular pressure (IOP) is a component in at least two visual system disorders. The first disorder is primary open angle glaucoma (POAG), which combines elevated IOP with a progressive optic neuropathy and results in characteristic excavation of the optic nerve head and corresponding visual field defects. The second disorder is ocular hypertension (OHT), in which IOP is elevated but no glaucomatous damage to the optic nerve head is observed and the detectable visual field does not change. Elevated IOP is a critical risk factor in the development of glaucomatous optic neuropathy [Armaly, 1980] and other visual field disorders. For example, between 4% [Kass, 2002] and 20% [Ontoso, 1997] of people with OHT will develop visual field defects within five years.
Although elevated IOP is a component in POAG, some other forms of glaucoma do not involve elevated IOP. Normal tension glaucoma (NTG) is a clinical entity characterized by similar damage of the optic nerve head and similar visual field defects, but without an elevated IOP. POAG is arbitrarily distinguished from NTG using a cut-off point of IOP of 21 mmHg [Vass, 2007].
Ocular hypertension is the strongest known risk factor for POAG. Intraocular pressure (IOP) is determined by aqueous humor (AqH) production in the ciliary body and by AqH drainage through the trabecular meshwork (TM) and uveoscleral drainage pathways. Elevated IOP occurs as a result of increased resistance to drainage of AqH primarily through the conventional outflow system and is associated with the increased extracellular matrix (ECM) deposition and decreased cellularity [Clark, 2003].
However, the normal regulation of IOP and retinal ganglion cell function remains largely unknown. A general lack of knowledge exists regarding the cellular and biochemical mechanisms behind IOP and OHT, making it difficult to identify the molecular events responsible for OHT. There is little understanding of the genetics of POAG and even less knowledge of the cell biology underlying it [Tan, 2006].
The main goal of treatment for all forms of glaucoma is the preservation of visual function. The cornerstone of therapy to achieve this goal is the reduction of IOP. Lowering IOP remains the mainstay of therapy in the management of glaucoma, since it has been shown to be effective in reducing optic nerve damage and thus the loss of visual field [Kaufman, 2006]. All antiglaucoma drugs currently in clinical use could be classified into two categories according to their mechanism of action on aqueous flow dynamism. One is the group of drugs suppressing aqueous production (α and β-adrenergic blockers, carbonic anhydrases inhibitors and Na+/K+-ATPase inhibitors) and the other is the group promoting aqueous outflow either by enhancing the pressure-sensitive (presumed trabecular) outflow pathway (cholinergics, MMP activators and protein kinase inhibitors) or by increasing the pressure-insensitive (uveoscleral) outflow (prostaglandins) [Clark, 2003; Institute, 2006; Orihashi, 2005; Marquis, 2005]. The assessment of the amount of flow through each pathway depends upon the measurement technique [Lim, 2008].
Conventional treatments of OHT, IOP and/or glaucoma have relied on the use of small molecules acting at receptors or acting as mediators in signaling pathways to enhance aqueous humor outflow or decrease aqueous inflow in order to lower IOP. In the current pharmacological treatment of glaucoma, five major classes of medications are presently available for clinical use. These include α-adrenergic agonists, β-adrenergic antagonists (β-blockers), carbonic anhydrase inhibitors (CAIs), cholinergics and prostaglandin (PG) compounds. The IOP is lowered either by decreasing the production of aqueous humor in the eye (α- and β-adrenergic blockers, carbonic anhydrases inhibitors and Na+/K+-ATPase inhibitors) or by improving its outflow either through the conventional pathway (through the canal of Schlemm such as cholinergics, MMP activators and protein kinase inhibitors) or through the uveoscleral outflow pathway (PGs) [Clark, 2003; Institute, 2006; Orihashi, 2005; Marquis, 2005]. Over the course of time, most patients will use more than one medication, singly and in varying combinations, experimenting with differing classes of compounds with varying mechanisms of action. All of the above-mentioned treatment agents have one or more serious and undesirable side effects [Kaufman, 2006].
Therefore, a need exists for a new class of effective IOP-lowering compounds which have minimal or beneficial side effects. The search for new, more effective and more selective compounds with fewer side effects for the treatment of ocular hypertension and glaucoma may also contribute to understanding the molecular mechanisms involved in the regulation of intraocular pressure.